2004 Fiscal Year Final Research Report Summary
Positional cloning of the pulmonary adenoma resistance 2 (Par2) locus of the mouse
| Project/Area Number |
14370083
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Experimental pathology
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| Research Institution | Okinaka Memorial Institute for Medical Research |
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Principal Investigator |
LEE Gang-hong Okinaka Memorial Institute for Medical Research, Senior Investigator, 主任研究員 (10261405)
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| Co-Investigator(Kenkyū-buntansha) |
KITAGAWA Tomoyuki Japanese Foundation for Cancer Research, Director, 癌研究所, 所長 (50085619)
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| Project Period (FY) |
2002 – 2004
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| Keywords | chimeric mouse / lung tumor / resistance locus / chromosome / cell autonomy / candidate gene / urethane |
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| Research Abstract |
The Pulmonary adenoma resistance 2 (Par2) locus of the BALB/cByJ mouse, located within 0.5 cM of chromosome 18, is responsible for reducing the mean multiplicity of urethane-induced lung tumors relative to those in C57BL/6J, A/J and C3H/HeJ mice. Thus, BALB/B6-Par2 congenic strain genetically identical to BALB/cByJ except carrying C57BL/6J Par2 alleles develops 7 times more tumors than BALB/cByJ. To gain clues for identification of Par2 candidate genes, we analyzed lung tumorigenesis in BALB/cByJ ⇔ BALB.B6-Par2 chimeric animals. Of 100 tumors induced by urethane in 16 chimeras, 82 originated from BALB.B6-Par2 cells, indicating the Par2 phenotype to be cell-autonomous. In addition, the BALB.B6-Par2- and BALB/cByJ-derived tumors were similar in mean size, implying that the phenotype is primarily expressed during initiation rather than in the promotion stage of carcinogenesis. Given these results, we surveyed a comprehensive mouse genome database and physically mapped Par2 within a 2.3 Mb
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p segment containing three known genes, Poli, Mbd2 and Dcc. Among those, the Poli seemed to be the most reasonable Par2 candidate, since it encodes an extremely error-prone DNA polymerase preferentially incorporating G or T opposite template T in vitro, reminiscent of the Kras2 activation due to an A to G or T point mutation within codon 61 with which most urethane-induced lung tumors are initiated. Indeed, our sequencing of Poli cDNAs from BALB/cByJ, C57BL/6J, A/J and C3H/HeJ lungs revealed 21BALB/cByJ-specific single nucleotide polymorphisms in the coding region accompanied by 7 amino acid substitutions and an elevated frequency of alternative splicing, while no polymorphisms associated with tumor susceptibility were found for either Mbd2 or Dcc. Notably, we obtained evidence that BALB/cByJ Par2 alleles may selectively decrease the frequency of kras2-mutated tumors compared with C57BL/6J alleles. Consequently, the Poli is an intriguing Par2 candidate clearly deserving further evaluation. Less
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Research Products
(5 results)
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[Journal Article] Analysis of lung tumorigenesis in chimeric mice indicates the Pulmonary adenoma resistance 2(Par2) locus to operate in the tumor-initiation stage in a cell-autonomous manner : detection of polymorphisms in the Poli gene as a candidate for Par2.2003
Author(s)
Lee, G.-H., Nishimori, H., Sasaki, Y., Matsushita, H., Kitagawa, T., Tokino, T.
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Journal Title
Oncogene 22
Pages: 2374-2382
Description
「研究成果報告書概要(欧文)」より
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